1. Optimized meropenem dosage regimens using a pharmacokinetic/pharmacodynamic population approach in patients undergoing continuous venovenous haemodiafiltration with high-adsorbent membrane
- Author
-
R Rigo Bonin, R Juvany Roig, XL Perez Fernandez, E. Leiva Badosa, J Sabater Riera, H Colom Codina, E. Sospedra Martínez, P Cardenas Campos, A Padullés Zamora, F Tubau Quintano, and P. Alia Ramos
- Subjects
Adult ,Male ,0301 basic medicine ,Microbiology (medical) ,medicine.medical_specialty ,Continuous Renal Replacement Therapy ,Critical Illness ,medicine.medical_treatment ,030106 microbiology ,Population ,Urology ,Microbial Sensitivity Tests ,030226 pharmacology & pharmacy ,Meropenem ,Sepsis ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,medicine ,Humans ,Pharmacology (medical) ,Prospective Studies ,Renal replacement therapy ,education ,Aged ,Aged, 80 and over ,Pharmacology ,education.field_of_study ,business.industry ,Middle Aged ,medicine.disease ,Anti-Bacterial Agents ,NONMEM ,Infectious Diseases ,Concomitant ,Pharmacodynamics ,Pseudomonas aeruginosa ,Female ,business ,Monte Carlo Method ,medicine.drug - Abstract
Background The pharmacokinetics (PK) of antibiotics change during sepsis and continuous renal replacement therapies in critically ill patients. Limited evidence exists on the use of the oXiris® high-adsorbent membrane. Objectives To develop a PK/pharmacodynamic (PD) model for meropenem in critically ill sepsis patients undergoing continuous venovenous haemodiafiltration (CVVHDF) with the oXiris® membrane, and to design an optimal dosing regimen assessed according to the PTA. Methods A prospective, open-label, observational PK trial was performed (EUDRACT 2011-005902-30). We conducted PK studies (plasma and ultrafiltrate) for at least 24 h after concomitant administration of CVVHDF and meropenem 1 g q8h. We constructed a PK model using the non-linear mixed-effects approach (NONMEM 7.3). We evaluated the suitability of different dosage regimens using Monte Carlo simulations and calculated the PTA as the percentage of subjects achieving a given percentage of time above the MIC (fT>MIC). Results The PK of meropenem was best captured by a two-open-compartment model with zero-order input kinetics and first-order elimination. Extracorporeal CL was 7.78 L/h [relative standard error (RSE) 16.45 L/h] and central compartment V (Vc) was 24.9 L (RSE 13.73 L). Simulations showed that, for susceptible Pseudomonas aeruginosa isolates (EUCAST MIC ≤2 mg/L) and attainment of 100%fT>MIC, 500 mg q8h given as extended (EI) or continuous infusion (CI) would be sufficient. For a target of 100%fT>4×MIC, CI of 3000 mg q24h or 2000 mg q8h administered as EI or CI would be required. Conclusions We have constructed a PK model of meropenem in sepsis patients undergoing CVVHDF using the oXiris® membrane. This tool will support physicians when calculating the optimal initial dose.
- Published
- 2019